The prevention of H. influenzae type b, (Hib), pneumococcal and meningococcal infections would be a major advance. These organisms are the major bacterial causes of meningitis, blood stream infection, pneumonia and middle ear infections in children and adults. The work accomplished during the first two years of this grant has demonstrated the feasibility of preparing a human hyperimmune globulin (termed Bacterial Polysaccharide Immune Gobulin okr BPIG) high concentrations of antibody against these organisms. The pharmacologic studies indicate that "protective" antibody levels to Hib are maintained for at least 4 months after a single im dose. Passive BPIG prophylaxis therefore has a high probability of success. Even if capsular polysaaccharide vaccines of improved immunogenicity can be developed, passive prophylaxis used instead of or in conjuction with active immunization is likely to be useful in selected high-risk children. We propose to continue our investigations by preparing sufficient BPIG for additional pharmaclogic studies and large-scale efficacy trials in the prevention of bacteremia meningitis, pneumonia, and recurrent otitis media. In addition, we will optimize methods of production by immunizing donors with new maximally immunogenic vaccines and evaluate genetic markers which identify donors with high and persistent IgG-class antibody responses. We will develop guidelines for standardizing the specific antibody concentrations required in the final globulin. An intravenous formulation of BPIG will be evaluated in humans. Experimental studies will be done to evaluate the safety and efficacy of hyperimmune globulin in the treatment of establishd Hib infections. Finally, we will exploit the availability of large volumes of human hyperimmune plasma by purifying IgG, IgM and IgA immunoglobulins and examining their actions and interactions against Hib in bactericidal and opsonophagocytic assays and in animal models.